Theacetylcholineneurotransmittersystemplaysanimportantroleinthemaintenanceofnormalphysiology suchasmemoryfunction,anditsdysregulation/dysfunctionhasbeenimplicatedinavarietyofneurologicaland psychiatric disease, especially in cognitive impairments associated with Alzheimer?s disease (AD) and schizophrenia.Themuscarinicacetylcholinereceptors(mAChRs)areimportanttargetsfordrugdevelopmentin AD and schizophrenia. Agonists at the orthosteric or allosteric sites of the M1 subtype receptor are currently underdevelopmentasdrugsforthetreatmentofcognitivedeficits.PositronEmissionTomography(PET)isa non-invasiveimagingtechniquethatallowstheinvivoinvestigationofneuroreceptorsinthelivingbodyandin receptor occupancy studies of emerging drugs. The availability of PET imaging agents selective for the M1 AChR will provide a non-invasive biomarker to interrogate this receptor subtype in vivo in humans and gain insights into its function and dysfunction in diseases. Further, PET imaging with an M1 AChR selective radiotracercanbeusedasaninvivobiomarkertoassesstargetengagementandcorrelatetargetoccupancy, doseexposureandtherapeuticresponseofemergingM1AChR-targetingdrugsinclinicaltrials,thusaidingthe developmentofnoveltherapeuticagents. Therehavebeennopriorreportsofvalidated,selectivePETradiotracersforuseinhumanstoimageM1 AChR.WearethefirsttocarryouttheradiosynthesisofaselectiveM1AChRradiotracer,11C-EMO,and evaluateditinnon-humanprimates.FurtherwehaveperformedpreliminarycharacterizationofthisnovelPET radiotracerinhumansanddemonstrateditsusefulnesstoimageandquantifyM1AChRavailabilityinthe brain.Inthisapplication,weproposetofullyvalidate11C-EMOfortheimagingandquantificationofM1AChR inhumansandfordetectionofchangesinsynapticacetylcholineconcentrations.Ourultimategoalisto providethebiomedicalimagingcommunitywithanoptimal,selectivePETradiotracerforinvivoimagingofM1 AChRinhumans.ThedevelopmentandsuccessfuldeploymentofasuitablePETimagingagentforM1AChR willenable,forthefirsttime,theinvivoinvestigationofthisreceptorsubtypeinpsychiatricandneurological diseases,anddrugoccupancystudiesofemergingM1AChRtargetingtherapeuticagents.